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<p>The application of messenger RNA (mRNA) beyond infectious diseases is challenged by inefficient protein production. Whereas the engineering of secondary mRNA structures has been shown to increase mRNA half-life, it remains unclear whether tertiary mRNA structures influence therapeutic efficacy. Here we develop a metal-ion-assisted RNA folding (MARF) strategy and show that, when delivered with lipid nanoparticles (LNPs), specific metals promote mRNA folding architectures that result in the amplification of protein expression by up to 7.3-fold compared with control mRNA. This effect is due to altered mechanical interactions between the mRNA LNPs and the surrounding biosystem, resulting in enhanced intracellular processing and prolonged retention of delivered mRNA in targeted cells. Administered intravenously, MARF LNPs achieved effective and durable genome editing of the clinically relevant <i>Pcsk9</i> gene through treatment with a single dose. Overall, this work provides a new MARF technology for more effective mRNA therapy and highlights the potential of mechanical cues in designing nanoparticles for improved mRNA delivery.</p>

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Rational design of rigid mRNA folding architecture to enhance intracellular processing and protein production

  • 期刊论文

  • 发表日期：

    2026年3月2日

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  • Bowei Yang,
  • Benhao Li,
  • Youliang Zhu,
  • Mengyao Zhao,
  • Yuanqi Cheng,
  • Xiaodan Zhao,
  • Deryn Teoh En-Jie,
  • Yifan Wang,
  • Miao Zhang,
  • Xianglong Tang,
  • Shuang Jin,
  • Yibin Sun,
  • Xuanbo Zhang,
  • Bin Xue,
  • Jie Yan,
  • Guanglu Wu,
  • Zhewang Lin,
  • Min Luo,
  • Haojie Yu,
  • Longjiang Zhang,
  • Xiaoyuan Chen,
  • Qianqian Ni

摘要

The application of messenger RNA (mRNA) beyond infectious diseases is challenged by inefficient protein production. Whereas the engineering of secondary mRNA structures has been shown to increase mRNA half-life, it remains unclear whether tertiary mRNA structures influence therapeutic efficacy. Here we develop a metal-ion-assisted RNA folding (MARF) strategy and show that, when delivered with lipid nanoparticles (LNPs), specific metals promote mRNA folding architectures that result in the amplification of protein expression by up to 7.3-fold compared with control mRNA. This effect is due to altered mechanical interactions between the mRNA LNPs and the surrounding biosystem, resulting in enhanced intracellular processing and prolonged retention of delivered mRNA in targeted cells. Administered intravenously, MARF LNPs achieved effective and durable genome editing of the clinically relevant Pcsk9 gene through treatment with a single dose. Overall, this work provides a new MARF technology for more effective mRNA therapy and highlights the potential of mechanical cues in designing nanoparticles for improved mRNA delivery.